The objective of this project (2) is to characterize essential correlates of chlamydial infection of the human reproductive tract in the human reproductive tract. This will prime effective translational research through the identification and characterization of chlamydial antigens of relevance to vaccine development and of physiologic or pathogenetic mechanisms that are at play in the complex, natural environment of the female genital tract and provide targets for possible chemotherapeutic intervention. The project involves extensive collaboration with the complementary projects 1 and 3 of the CRC and will rely on Cores B, C and D for the provision of guinea pig and human sera and swabs, and biostatistical analysis of the results, respectively. In a first phase, the virulence of C. trachomatis and C. caviae genital isolates will be quantified in relationship to genome sequence type and reproductive tract ecology using a patient cohort representative of genital chlamydial disease in humans. Virulence will be measured using genomic doubling, infectious yield, inclusion fusogenicity and pathology as measurable physiological/pathogenic traits or endpoints, and using biomathematical modeling of Intracellular development and correlated pathology. A second phase of the research will be to investigate in relationship to genome sequence type and reproductive tract ecology the functional diversity of two gene families of C. trachomatis and C. caviae encoding inclusion membrane proteins (Inc) and effector proteins of the virulence-associated type III secretion (T3S) system that are targets for possible chemotherapeutic intervention. The developmental expression of selected inc and T3S effector genes in variants of C. trachomatis and C. caviae will be characterized and subcellular and molecular targets of variant Inc and T3S effector proteins will be identified. Finally, the diversity of the vaccine target pmp gene family and Pmp-specific antibody responses in C trachomatis -infected patients and C. caviae-infected guinea pigs will be investigated in relationship to genome sequence type and reproductive tract ecology. This will be achieved through characterization of the developmental expression of pmp genes in variants of C. trachomatis and C. caviae, profiling the high frequency on/off switching of Pmp expression in selected variants and performing cross-sectional and longitudinal investigations of the Pmp-specific antibody response comparatively in infected humans and guinea pigs.